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Although RXFP1-cAMP signaling in HEK293T cell systems is now relatively well-defined, the signaling pathways activated by relaxin in its target cells and tissues are still unclear. This study aimed to examine the cAMP signaling of RXFP1 in cells that endogenously express the receptor. Seven cell types derived from various backgrounds were screened for receptor expression. Only in THP-1 cells and rat cardiac fibroblasts was there activation of the Gαi3–Gβγ–phosphatidylinositol 3-kinase–protein kinase Cζ pathway, leading to cAMP accumulation. In all other cells there was activation of a combination of the initial pathways to affect cAMP. T-47D cells could activate only Gαs, whereas Colo 16 and rat renal fibroblasts from obstructed kidney could activate both Gαs and GαoB pathways. Thus, the signaling pathways activated by relaxin are highly dependent upon the cell type under investigation, and this may help to explain the varied physiological responses exerted by relaxin in its different target tissues. [ABSTRACT FROM AUTHOR]

Abstract: Mitofusin-2 (Mfn2) suppresses smooth muscle cell proliferation through inhibition of the Ras-extracellular signal-regulated kinases (ERK1/2) pathway. Since the ERK1/2 pathway is implicated in mediating hypertrophic signaling, we studied the changes in Mfn2 in cardiac hypertrophy using in vitro and in vivo models. Phenylephrine was used to induce hypertrophy in neonatal rat ventricular myocytes (NRVMs). In vivo hypertrophy models included spontaneously hypertensive rats (SHR), pressure-overload hypertrophy by transverse aortic constriction (TAC), hypertrophy of non-infarcted myocardium following myocardial infarction (MI), and cardiomyopathy due to cardiac-restricted overexpression of β2-adrenergic receptors (β2-TG). We determined hypertrophic parameters and analysed expression of atrial natriuretic peptide (ANP) and Mfn2 by real-time PCR. Phosphorylated-ERK1/2 (phospho-ERK) was measured by Western blot. Mfn2 was downregulated in phenylephrine treated NRCMs (by ∼40%), hypertrophied hearts from SHR (by ∼80%), mice with TAC (at 1 and 3 weeks, by ∼50%), and β2-TG mice (by ∼20%). However, Mfn2 was not downregulated in hypertrophied hearts with 15 weeks of TAC, nor in hypertrophied non-infarcted myocardium following MI. phospho-ERK1/2 was increased in hypertrophied myocardium at 1 week post-TAC, but not in non-infarcted myocardium after MI, indicating that downregulated Mfn2 may be accompanied by an increase of phospho-ERK1/2. This study shows, for the first time, downregulated Mfn2 expression in hypertrophied hearts, which depends on the etiology and time course of hypertrophy. Further study is required to examine the causal relationship between Mfn2 and cardiac hypertrophy. [Copyright &y& Elsevier]

Cardiac RXFP1 was upregulated upon activation of the α1-adrenergic receptor (AR) through signal pathways involving protein kinase A and C and ERK. In contrast, β1-AR activation downregulated expression of cardiac RXFP1 and it further counteracted the α1-AR-mediated RXFP1 upregulation. [ABSTRACT FROM AUTHOR]